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  2. Integrative Analysis of Proteome and Ubiquitylome Reveals Unique Features of Lysosomal and Endocytic Pathways in Gefitinib-Resistant Non-Small Cell Lung Cancer Cells

Integrative Analysis of Proteome and Ubiquitylome Reveals Unique Features of Lysosomal and Endocytic Pathways in Gefitinib-Resistant Non-Small Cell Lung Cancer Cells

  • Proteomics. 2018 Aug;18(15):e1700388. doi: 10.1002/pmic.201700388.
Wang Li 1 Heyong Wang 1 Yan Yang 1 Tian Zhao 1 Zhixiong Zhang 1 Ye Tian 1 Zhaomie Shi 2 Xiaojun Peng 2 Fei Li 3 Yonghong Feng 1 Lei Zhang 1 Gening Jiang 1 Fan Zhang 1
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, School of Life Science and Technology, Tongji University, Shanghai, 200433, P. R. China.
  • 2 Jingjie PTM BioLab Co. Ltd., Hangzhou Economic and Technological Development Area, Hangzhou, 310018, P. R. China.
  • 3 Department of Biology, New York University, New York, NY, 10003, USA.
Abstract

Non-small cell lung Cancer (NSCLC) patients carrying EGFR activating mutations treated with gefitinib, a tyrosine kinase inhibitor, will develop drug resistance. Ubiquitylation is one of major posttranslational modifications of proteins affecting the stability or function of proteins. However, the role of protein ubiquitylation in gefitinib resistance is poorly understood. To systematically identify the global change in protein expression and ubiquitylation during gefitinib resistance, a quantitative global proteome and ubiquitylome study in a pair of gefitinib-resistant and sensitive NSCLC cells is carried out. Altogether, changes in expression of 3773 proteins are quantified, and changes in ubiquitylation of 2893 lysine sites in 1415 proteins are measured in both cells. Interestingly, lysosomal and endocytic pathways, which are involved in Autophagy regulation, are enriched with upregulated proteins or ubiquitylated proteins in gefitinib-resistant cells. In addition, HMGA2 overexpression or ALOX5 knockdown suppresses gefitinib resistance in NSCLC cells by inhibiting Autophagy. Overall, these results reveal the previously unknown global ubiquitylome and proteomic features associated with gefitinib resistance, uncover the opposing roles of HMGA2 or ALOX5 in regulating gefitinib resistance and Autophagy, and will help to identify new therapeutic targets in overcoming gefitinib resistance.

Keywords

gefitinib resistance; non-small cell lung cancer; proteome; ubiquitylome.

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